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Diabetologia

, Volume 50, Issue 4, pp 741–746 | Cite as

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

  • J. M. M. Howson
  • D. B. Dunger
  • S. Nutland
  • H. Stevens
  • L. S. Wicker
  • J. A. Todd
Article

Abstract

Aims/hypothesis

HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without.

Materials and methods

TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1.

Results

TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR] = 1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI = 1.29–1.72) than did the TPOAbs-negative patients (p = 0.0004; OR = 1.16; 95% CI = 1.10–1.24) or type 1 diabetes patients overall (OR = 1.20; 95% CI = 1.13–1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p = 1.86 × 10−15). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601).

Conclusions/interpretation

Our results identify a subgroup of type 1 diabetic patients that is sensitive to allelic variation of the negative regulatory molecule CTLA-4 and indicate that TPOAbs testing could be used to subclassify type 1 diabetes patients for inclusion in genetic, biological or clinical studies.

Keywords

Autoimmunity CTLA-4 Diabetes Human Thyroid antibodies 

Abbreviations

AITD

autoimmune thyroid disease

APS

autoimmune polyendocrine syndrome

CTLA-4

cytotoxic T-lymphocyte-associated antigen-4

liCTLA4

ligand-independent form of CTLA-4

NOD

non-obese diabetic

OR

odds ratio

PTPN22

protein tyrosine phosphatase non-receptor type 22 (lymphoid)

SNP

single nucleotide polymorphism

TPOAbs

thyroid peroxidase autoantibodies

Introduction

Autoimmune diseases, a failure of immune tolerance to self antigens, are strongly inherited and often co-occur in the same patients or families [1, 2, 3, 4, 5], probably due to sharing of susceptibility alleles across multiple loci [6] and to environmental factors [7, 8]. In particular, autoimmune thyroid disease (AITD) (Graves’ disease and Hashimoto thyroiditis associated with hyper- and hypothyroidism, respectively) and autoimmune type 1 diabetes are often diagnosed in the same subjects [1, 2, 4, 9, 10].

In addition to associations with HLA class II alleles and haplotypes, notably DRB1*03-DQB1*02 [10, 11, 12], and the lymphoid-specific phosphatase T cell activation gene, protein tyrosine phosphatase non-receptor type 22 (lymphoid) (PTPN22) [13], AITD and type 1 diabetes have been associated with the cytotoxic T-lymphocyte-associated antigen-4 gene (CTLA4) [5], which encodes a vital negative immunoregulatory receptor in T cell activation and expansion. The association with AITD is strong (odds ratio [OR] ∼1.5) with single nucleotide polymorphisms (SNPs) in the 3′UTR of the gene being the strongest candidates for the causal variant(s) [14]. The SNP most associated with disease is rs3087243 (with aliases 6230G>A and CT60) [14]. However, the effect is much smaller in type 1 diabetes (OR ∼ 1.15–1.2) [15]. Indeed, a recent study of 769 Japanese type 1 diabetes patients, 345 of which were diagnosed with AITD [16], claimed that CTLA4 is only associated with AITD and that the association with type 1 diabetes is secondary to anti-thyroid autoimmunity such that the G allele of the CTLA4 rs3087243 SNP does not have any direct effect on susceptibility to type 1 diabetes. However, the reported differences were not statistically significant. In three other studies, CTLA4 was reported to be associated with co-occurrence of type 1 diabetes and AITD [5, 17, 18], which is a form of autoimmune polyendocrine syndrome (APS) [2, 19].

Autoantibodies to components of the thyroid gland, including thyroid peroxidase autoantibodies (TPOAbs), often precede diagnosis of AITD [4, 20], and CTLA4 is associated with TPOAbs production [21]. In the USA, 4.8% of individuals aged 12 to 19 years have TPOAbs [22], whereas 10 to 30% of patients with type 1 diabetes have thyroid antibodies, up to 50% of whom progress to clinical AITD [19].

We collected plasma and DNA samples from more than 4,000 patients with type 1 diabetes, mostly from paediatric clinics from across Great Britain, with a view to investigating the association of CTLA4 in type 1 diabetes patients subclassified into patients with TPOAbs and those without.

Subjects and methods

Subjects

We studied 4,364 type 1 diabetes patients from Great Britain, mostly diagnosed under the age of 16 years, with a mean (± SD) of 7.5 (±3.9) years. In these patients, plasma TPOAbs levels were measured. Geographically matched control subjects (n = 6,866) were from the 1958 British Birth Cohort [13]. Approval from the relevant ethics committee was sought before DNAs were collected and written informed consent obtained from all participants or their parents/guardians for those too young to give consent. This investigation was carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000. TPOAbs in the type 1 diabetes patients was measured by ELISA (PLATO processor; Phadia [formerly Sweden Diagnostics], Milton Keynes, UK). Recombinant TPO antigen was used, standardised against the National Institute of Biological Standards and Controls standard sera 66/387. Individuals were considered positive for TPOAbs above 85 IU/ml.

Genotyping

The rs3087243 (+6230G>A) SNP in CTLA4 was genotyped in all samples because it was the variant most associated with both type 1 diabetes and AITD in a recent study [14]. Genotyping was done using TaqMan MGB chemistries (Applied Biosystems, Warrington, UK). Details of the genotyping of the SNPs of PTPN22 (Arg620Trp; rs2476601) and the insulin gene (INS) (rs689) have been described previously [13, 23]. HLA-DRB1 and -DQB1 were typed in a subset of these British patients using the Dynal–Roche system (Dynal Biotech, Wirral, UK).

We successfully genotyped and measured TPOAbs in type 1 diabetic patients as follows: 3,998 patients at CTLA4, 4,219 patients at INS, 4,203 patients at PTPN22, 2,034 patients at HLA-DQB1 and 1,952 patients at HLA-DRB1. We also had genotypes for 6,866 control subjects at CTLA4.

Statistical methods

Logistic regression was used to test for association and to calculate ORs, with 95% CIs, using STATA8 (www.stata.com) and the rs3087243 A/A genotype as reference at OR = 1.0. As patients and control subjects were collected from across Great Britain, analyses were stratified according to 12 geographical regions by putting a regional variable into the regression [24]. In this way any confounding due to variation in allele frequency across Britain was minimised. To test for an interaction effect between genotype (at rs3087243, PTPN22 or INS) or haplotype (HLA-DRB1_HLA-DQB1) and the presence of TPOAbs in type 1 diabetic patients, a patient-only logistic regression approach was adopted with TPOAbs status as the outcome variable. We also tested whether the subject’s sex explained the variation in TPOAbs by regressing sex on TPOAbs status. Sex was found to be an important determinant of TPOAbs status and so was included as a confounder in all analyses of TPOAbs by including a sex variable in the regression.

Results

Thyroid autoantibodies in type 1 diabetes

Of 4,364 patient samples tested, 462 (10.6%) were TPOAbs-positive, which is similar to previous studies [4, 5]. The ratio of women:men was significantly elevated in the TPOAbs-positive patients (1.94:1) compared with the TPOAbs-negative patients (0.86:1) or the type 1 diabetes patients overall (0.94:1) (Table 1). Female type 1 diabetes patients are more likely to have TPOAbs (OR = 2.31; 95% CI = 1.87–2.85; p = 1.86 × 10−15) (Table 1). The mean age at diagnosis of diabetes did not differ between the TPOAbs-positive (7.6 years) and negative patients (7.5 years; p = 0.16) (Table 1, Fig. 1), with median ages at type 1 diabetes diagnosis of 8 and 7 years, respectively (Table 1, Fig. 1). In the TPOAbs-positive subgroup there was no difference between females and males in the age at diagnosis of type 1 diabetes (means 7.71 and 7.50 years; ranges 1–16 and 1–21). There was no effect of duration of type 1 diabetes on the presence of TPOAbs (p = 0.73) once age at blood donation was accounted for in the regression model.
Table 1

Phenotypes of the type 1 diabetic subgroups tested for thyroid autoantibodies

 

All type 1 diabetes patients

TPOAbs-positive patients

TPOAbs-negative patients

p value

Women:men (n; %)

0.94:1 (2,112:2,251; 48.4:51.6)

1.94:1 (305:157; 66.0:34.0)

0.86:1 (1,767:2,060; 46.2:53.8)

1.86 × 10−15

Age at diagnosis of type 1 diabetes, mean (SD) (years)

 Overall

7.5 (3.9)

7.6 (4.1)

7.5 (3.9)

0.16

 Male

7.5 (4.0)

7.5 (4.5)

7.5 (4.0)

 

 Female

7.5 (3.8)

7.7 (3.8)

7.4 (3.8)

 

Median age at diagnosis of type 1 diabetes (years)

 Overall

7

8

7

NA

 Male

7

7

7

 

 Female

7

8

7

 

NA, not applicable

Fig. 1

Frequency distribution of age at diagnosis of type 1 diabetes by thyroid antibodies status in 1-year intervals. Beige, TPOAbs-negative; red, TPOAbs-positive

Genetic control of type 1 diabetes with thyroid autoantibodies

With regard to CTLA4, we observed a convincing difference between TPOAbs subgroups (p = 0.0004) (Tables 2, 3 and 4), with a 6.2% increase in the frequency of the disease-associated G allele of rs3087243 in the TPOAbs-positive group (Table 2) and almost twice the risk of having both type 1 diabetes and TPOAbs associated with the G allele or G/G genotype (OR of the G/G genotype = 2.63 in the TPOAbs-positive group compared with 1.37 in the TPOAbs-negative group, with no overlap in the 95% CIs) (Table 4).
Table 2

Genetic associations in thyroid autoantibodies-positive and -negative British type 1 diabetes patients

 

Number of patientsa

Frequency (%) in TPOAbs-positive patients

Frequency (%) in TPOAbs-negative patients

Frequency (%) in womenb

Frequency (%) in menb

p difference

CTLA4 rs3087243 (G>A)

3,998

64.5

58.6

48.6

51.4

0.0004

DRB1*03_DQB1*02

1,956

38.8

33.7

47.7

52.3

0.02

DRB1*03_DQB1*02/DRB1*03_DQB1*02

198

7.8

3.9

44.4

55.6

0.05

DRB1*0401_DQB1*0302

1,956

20.3

24.9

47.0

53.0

0.72

DR3/4 (not DRB1*0403)

2,046

32.0

34.1

47.5

52.5

0.52

DRB1*15_DQB1*0602

1,956

0.7

0.2

36.4

63.6

0.02

INS-23HphI rs689

4,219

14.9

15.4

48.4

51.6

0.63

PTPN22 rs2476601

4,203

19.6

16.9

48.3

51.7

0.06

aThese are the numbers of patients with TPOAbs measures who were also genotyped at the locus listed. Sex and age at donation of blood are included in tests of statistical differences between the TPOAbs-positive and -negative subgroups.

bFor the HLA-DRB1 and -DQB1 haplotypes, percentages are based on the most likely haplotype assignment.

Table 3

Allele and genotype frequencies at CTLA4 rs3087243 in type 1 diabetic and Graves’ patients

Allele/genotype

All type 1 diabetes patients [n (%)]

TPOAbs-positive [n (%)]

TPOAbs-negative [n (%)]

Graves’ patients [n (%)]

Control subjects [n (%)]

G

4,819 (59.3)

560 (64.5)

4,174 (58.6)

835 (63.4)

7,523 (54.8)

A/A

663 (16.3)

44 (10.1)

611 (17.1)

90 (13.7)

1,431 (20.8)

A/G

1,987 (48.9)

220 (50.7)

1,732 (48.6)

301 (45.7)

3,347 (48.8)

G/G

1,416 (34.8)

170 (39.2)

1,221 (34.3)

267 (40.6)

2,088 (30.4)

Table 4

Odds ratios with 95% CIs at CTLA4 rs3087243 for all type 1 diabetic patients and by TPOAbs positivity compared with Graves’ patients

Allele/genotype

All type 1 diabetes patients

TPOAbs-positive patientsa

TPOAbs-negative patients

Graves’ disease patients b

OR (95% CI)

p value

OR (95% CI)

p value

OR (95% CI)

p value

OR (95% CI)

p value

Gc

1.20(1.13–1.27)

3.71 × 10−10

1.49(1.29–1.72)

4.08 × 10−8

1.16 (1.10–1.24)

5.54 × 10−7

1.37 (1.19–1.57)

6.25 × 10−6

A/A

1.00 (ref)

 

1.00 (ref)

 

1.00 (ref)

 

1.00 (ref)

 

A/G

1.30 (1.16–1.45)

8.66  × 10−10

2.16 (1.55–3.01)

1.03 × 10−8

1.23 (1.09–1.38)

2.10 × 10−6

1.32 (0.99–1.74)

0.00004

G/G

1.47 (1.31–1.66)

 

2.63 (1.87–3.70)

 

1.37 (1.22–1.55)

 

1.85 (1.39–2.47)

 

aA two degree of freedom genotype test should be used here as the multiplicative model is inappropriate p = 0.0097.

bIn the Graves’ disease analysis, the patients, who are from a previous study [14] and were not collected from all 12 sub-regions of Great Britain, were matched to 1,745 control subjects from the regions of their origin.

cAllele A is used as reference (ref).

One other interesting difference observed by us in the association of CTLA4 with the TPOAbs-positive type 1 diabetes patients, was the mode of inheritance of the locus: the disease risk of the alleles did not fit with the multiplicative model, as seen in both type 1 diabetes and AITD (Table 4) (p = 0.0097 against this model); instead, the G allele had a dominant effect with no significant difference between the G/A heterozygote (OR = 2.16) and the G/G homozygous genotype risks (OR = 2.63) (Table 4). Note that the CTLA4 rs3087243 G allele did not affect age at diagnosis of type 1 diabetes overall (p = 0.18) or of type 1 diabetes in TPOAbs-positive patients (p = 0.67), nor was it differentially associated in females and males (p = 0.61).

We also tested whether the other susceptibility genes established to be associated with type 1 diabetes and AITD, namely HLA-DRB1, HLA-DQB1, INS and PTPN22, were differentially associated with the two disease subgroups (Table 2). No convincing evidence of an interaction between TPOAbs-positivity and alleles, genotypes or haplotypes of these genes was obtained (Table 2).

Discussion

Our results indicate that certain type 1 diabetic patients suffer from an immune tolerance defect to both the insulin-producing beta cell and the thyroid gland, which can occur very early in life, since TPOAbs are present in the youngest of type 1 diabetic patients (Fig. 1). This form of disease is strongly regulated by allelic variation in CTLA4. This conclusion is consistent with the critical role of CTLA4 in peripheral tolerance as an inhibitory regulator of T cell activation, T cell proliferation and apoptosis, as well as its roles in the functions of antigen presenting cells and T regulatory cells [25, 26, 27]. We have proposed that a reduced function of CTLA4 associated with the rs3087243 G allele allows T cells to be more hyperactive and to respond to peripheral antigens to a greater degree than individuals carrying the rs3087243 SNP A/A genotype, which is associated with autoimmune disease protection and increased peripheral tolerance [14, 28]. However, our results also indicate that allelic variation of CTLA4 has a much smaller effect in approximately 90% of type 1 diabetic patients. Previous studies have reported that in excess of 15% of European type 1 diabetic patients develop anti-thyroid autoimmunity [19]. Thus if we had been able to detect these within our patient samples, the OR in the TPOAbs-negative subgroup would probably have decreased to 1 or very close to it. Our interpretation of this result is different from a recent Japanese study, which concluded that CTLA4 is only associated with AITD in type 1 diabetic patients [16] and that the association with type 1 diabetes is secondary to anti-thyroid autoimmunity such that the G allele of the CTLA4 rs3087243 SNP does not have any direct effect on susceptibility to type 1 diabetes.

We suggest that allelic variation of CTLA4 does directly affect type 1 diabetes by predisposing individuals with a G allele to reduced levels of tolerance to a multiplicity of peripheral antigens and maybe even a form of APS (the occurrence in patients of two or more endocrine autoimmune diseases). We also note that in patients with both type 1 diabetes and AITD, type 1 diabetes nearly always occurs more than a decade before the development of clinical AITD. However, the strongest evidence for a direct effect of allelic variation of CTLA4 on type 1 diabetes susceptibility is provided by studies in the non-obese diabetic (NOD) mouse [14, 29, 30, 31]. Genetic analysis of the NOD mouse model of type 1 diabetes has shown that the region of mouse chromosome 1 containing Ctla4 and the insulin dependent diabetes susceptibility 5a (Idd5a, previously known as Idd5.1) locus has a significant effect on disease susceptibility [14, 29, 30, 31]. The causal variant has been mapped to a SNP in exon 2 of Ctla4, for which the NOD allele reduces the splicing and production of an alternative mRNA isoform of CTLA4, the ligand-independent form (liCTLA4) [14]. Moreover, it has been shown that liCTLA4 has inhibitory functions in T cell activation [29].

NOD mouse studies have also shown that different combinations of alleles of multiple susceptibility genes can lead to a variety of autoimmune phenotypes, including liver disease and AITD, as well as type 1 diabetes with different rates of progression [32] (K. Hunter, J. A. Todd, L. S. Wicker, unpublished data). In particular, the effect of resistance alleles in mouse Ctla4 is masked when resistance alleles at a separate disease locus are present in the mouse and when, in a separate susceptibility gene combination, the resistance allele in mouse Ctla4 can completely mask the potent disease-causing effect of a particular susceptibility allele at another locus. It has also been shown that a third locus, insulin dependent diabetes susceptibility 3 (Idd3), which is believed to be the interleukin-2 gene [32, 33] can influence the production of CTLA-4 [30, 34]. We, therefore, propose that AITD, type 1 diabetes and co-occurring type 1 diabetes and AITD manifest due to different, but overlapping combinations of susceptibility and resistance alleles of multiple loci, and that in isolated type 1 diabetes (up to 90% of cases) the constellations of alleles giving rise to this disease mask the allelically variable effect of CTLA4 to a much greater degree than the combination of alleles causing AITD or type 1 diabetes + TPOAbs as studied here.

It will be interesting to try to identify genes with alleles that can mask the effect of CTLA4 alleles in humans. At the same time, we cannot ignore the role of the yet-to-be-defined environmental and developmental factors in determining the penetrance of susceptibility genes. Finally, the bias in the proportion of female type 1 diabetic patients with TPOAbs is comparable with previous, small studies of 35 [5], 28 [18] and 77 [17] APS (type 1 diabetes + AITD) patients, in which the ratios of women:men were 1.7:1, 2.5:1 and 2.3:1, respectively, suggesting that X-linked factors are operating. One possibility is that the skewing of X inactivation, which has been described in AITD patients [35, 36], alters expression of immune genes on chromosome X, thereby predisposing to autoimmunity in females. We note in our data that the bias may begin in patients with age at diagnosis of less than 10 years, in whom the ratio of women:men in TPOAbs-positive type 1 diabetes cases was 1.28:1, compared with 0.88:1 in the TPOAbs-negative patients, occurring before the onset of puberty and therefore at an age when hormonal effects are unlikely to influence the penetrance of APS in females.

In conclusion, our study is unique in that it shows a statistically significant difference in: (1) the association between CTLA4 and type 1 diabetes patient subgroups; and (2) the ratio of women:men within these subgroups. Moreover, with regard to TPOAbs status, which is a routine clinical test, we have shown that the TPOAbs marker is present in many type 1 diabetic patients at a young age and could therefore be a useful and early biomarker for this subclass of type 1 diabetes. In ongoing clinical trials to reverse or retard type 1 diabetes, inter-individual genetic variation in the balance of immune effector responses and tolerance could be partially reflected by TPOAbs status, thereby making it a parameter that would positively correlate with a poor outcome for tolerance-inducing therapeutic intervention.

Notes

Acknowledgements

We thank the DNA team for the preparation of DNA and plasma samples. We acknowledge the assistance of D. Strachan, M. Pembrey, W. McArdle, S. Ring and Paul Burton in this project. L. S. Wicker and J. A. Todd are supported by grants from the Juvenile Diabetes Research Foundation and the Wellcome Trust. L. S. Wicker is a Juvenile Diabetes Research Foundation/Wellcome Trust Principal Research Fellow. We acknowledge use of DNA from the 1958 British Birth Cohort collection, funded by the Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02.

Duality of interest

The authors declare that they have no duality of interest.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • J. M. M. Howson
    • 1
  • D. B. Dunger
    • 2
  • S. Nutland
    • 1
  • H. Stevens
    • 1
  • L. S. Wicker
    • 1
  • J. A. Todd
    • 1
  1. 1.Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical ResearchUniversity of Cambridge, Wellcome Trust/MRC Building, Addenbrooke’s HospitalCambridgeUK
  2. 2.Department of PaediatricsUniversity of Cambridge, Addenbrooke’s HospitalCambridgeUK

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